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At least 217 records · Page 12Linked to original sources
PubMed2001

The two PDGF receptors maintain conserved signaling in vivo despite divergent embryological functions.

Gene targeting studies have indicated that the two receptors for PDGF, alpha and beta, direct unique functions during development. Distinct ligand affinities, patterns of gene expression, and/or mechanisms of signal relay may account for functional specificity of the two PDGF receptor isoforms. To distinguish between these factors, we have created two complementary lines of knockin mice in which the intracellular signaling domains of one PDGFR have been removed and replaced by those of the other PDGFR. While both lines demonstrated substantial rescue of normal development, substitution of the PDGFbetaR signaling domains with those of the PDGFalphaR resulted in varying degrees of vascular disease. This observation provides a framework for discussing the evolution of receptor tyrosine kinase functional specificity.

Animals↗
PubMed1989

Vertebrate and yeast calmodulin, despite significant sequence divergence, are functionally interchangeable.

Yeast strains relying solely on vertebrate (Xenopus laevis) calmodulin, expressed under control of a yeast (GAL1) promoter, grew at the same rate as yeast cells containing their endogenous calmodulin. Therefore, the ability to perform essential functions has been conserved between yeast and vertebrate calmodulins, suggesting that calmodulin performs the same (or overlapping) roles in yeast as it does in higher eukaryotes. Successful substitution of vertebrate for yeast calmodulin also suggests that the two proteins can adopt similar conformations in vivo, despite the large number of amino acid differences between them (60 out of 148 residues). Strains overproducing either vertebrate or yeast calmodulin about 100-fold and a strain producing a normal level of yeast calmodulin were essentially indistinguishable in many characteristics, including microtubule distribution, rate of secretion, response to mating pheromone, sporulation, and adaptation to nutrient limitation. Calmodulin overproduction did not confer elevated resistance to a phenothiazine drug, trifluoperazine, thought to be a calmodulin-specific inhibitor. These results have important implications for understanding the role of calmodulin in intracellular calcium signaling.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Amino acid substitution during functionally constrained divergent evolution of protein sequences.

In aligning homologous protein sequences, it is generally assumed that amino acid substitutions subsequent in time occur independently of amino acid substitutions previous in time, i.e. that patterns of mutation are similar at low and high sequence divergence. This assumption is examined here and shown to be incorrect in an interesting way. Separate mutation matrices were constructed for aligned protein sequence pairs at divergences ranging from 5 to 100 PAM units (point accepted mutations per 100 aligned positions). From these, the corresponding log-odds (Dayhoff) matrices, normalized to 250 PAM units, were constructed. The matrices show that the genetic code influences accepted point mutations strongly at early stages of divergence, while the chemical properties of the side chains dominate at more advanced stages.

Amino Acid Sequence↗
PubMed2006

Rhomboid proteins: conserved membrane proteases with divergent biological functions.

The rhomboid gene was discovered in Drosophila, where it encodes a seven transmembrane protein that is the signal-generating component of epidermal growth factor (EGF) receptor signaling during development. Although metazoan developmental regulators are rarely conserved outside the animal kingdom, rhomboid proteins are conserved in all kingdoms of life, but the significance of this remains unclear. Recent biochemical reconstitution and high-resolution crystal structures have provided proof that rhomboid proteins function as novel intramembrane proteases, with a serine protease-like catalytic apparatus embedded within the membrane bilayer, buried in a hydrophilic cavity formed by a protein ring. A thorough consideration of all known examples of rhomboid function suggests that, despite biochemical similarity in mechanism and specificity, rhomboid proteins function in diverse processes including quorum sensing in bacteria, mitochondrial membrane fusion, apoptosis, and stem cell differentiation in eukaryotes; rhomboid proteins are also now starting to be linked to human disease, including early-onset blindness, diabetes, and parasitic diseases. Regulating cell signaling is at the heart of rhomboid protein function in many, but not all, of these processes. Further study of these novel enzymes promises to reveal the evolutionary path of rhomboid protein function, which could provide insights into the forces that drive the molecular evolution of regulatory mechanisms.

Amino Acid Sequence↗
PubMed1997

Divergence of function and regulation of class B floral organ identity genes.

Regulatory mechanisms controlling basic aspects of floral morphogenesis seem to be highly conserved among plant species. The class B organ identity genes, which are required to establish the identity of organs in the second (petals) and third (stamens) floral whorls, are a good example of such conservation. This work compares the function of two similar class B genes in the same genetic background. The DEFICIENS (DEF) gene from Antirrhinum, including its promoter, was transformed into Arabidopsis and compared in function and expression with the Arabidopsis class B genes APETALA3 (AP3) and PISTILLATA (PI). The DEF gene was expressed in the second, third, and fourth whorls, as was PI. Functionally, DEF could replace AP3 in making petals and stamens. The DEF gene's AP3-like function and PI-like expression caused transformation of fourth-whorl carpels to stamens. Like AP3, all aspects of DEF function in Arabidopsis required a functional PI protein. Surprisingly, DEF could not replace the AP3 protein in properly maintaining AP3 transcripts (autoregulation). Our data allow us to revise the current model for class B autoregulation and propose a hypothesis for the evolution of class B gene expression in dicotyledonous plants.

Arabidopsis↗
PubMed2026

Thrombin concentration shapes endothelial extracellular vesicle profiles with divergent inflammatory functions.

Thrombin, a central enzyme in the coagulation cascade, also regulates diverse cellular processes, including inflammation and vascular barrier function, primarily by activating protease-activated receptor 1. Previous studies demonstrated that thrombin elicits concentration-dependent, opposing effects; low concentrations confer anti-inflammatory and barrier-protective responses, whereas high concentrations promote inflammation and barrier disruption. The underlying mechanisms, however, remain incompletely understood. Here, we showed that thrombin stimulates extracellular vesicle (EV) release from endothelial cells across a broad concentration range and that EVs generated at low vs high thrombin concentrations carry distinct microRNA (miR) cargo. Low-thrombin EVs mediate cytoprotective responses via the transfer of miR-409-5p, which targets ubiquitin-specific protease 7 that promotes inflammation via the NF-kB signaling pathway in recipient cells, whereas high-thrombin EVs disrupt barrier integrity and promote inflammation through delivery of miR-155-5p, a regulator of suppressor of cytokine signaling 1 that acts as a crucial negative regulator of the cytokine signaling pathway. Functional manipulation of these EVs confirmed the causal roles. Incorporation of anti-miR-409-5p abrogated the protective effects of low-thrombin EVs, whereas anti-miR-155-5p suppressed the cytopathic effects of high-thrombin EVs. Moreover, control EVs engineered to carry a miR-409-5p mimic reproduced the anti-inflammatory and barrier-protective phenotype of low-thrombin EVs. Collectively, these findings identified EV-associated miRs as key mediators of the concentration-dependent dual actions of thrombin, which may open the therapeutic potential of EVs engineered to deliver selective miRs or anti-miRs for the treatment of inflammatory vascular diseases.

Thrombin↗
PubMed2003

Functional tests of enhancer conservation between distantly related species.

Expression patterns of orthologous genes are often conserved, even between distantly related organisms, suggesting that once established, developmental programs can be stably maintained over long periods of evolutionary time. Because many orthologous transcription factors are also functionally conserved, one possible model to account for homologous gene expression patterns, is conservation of specific binding sites within cis-regulatory elements of orthologous genes. If this model is correct, a cis-regulatory element from one organism would be expected to function in a distantly related organism. To test this hypothesis, we fused the green fluorescent protein gene to neuronal and muscular enhancer elements from a variety of Drosophila melanogaster genes, and tested whether these would activate expression in the homologous cell types in Caenorhabditis elegans. Regulatory elements from several genes directed appropriate expression in homologous tissue types, suggesting conservation of regulatory sites. However, enhancers of most Drosophila genes tested were not properly recognized in C. elegans, implying that over this evolutionary distance enough changes occurred in cis-regulatory sequences and/or transcription factors to prevent proper recognition of heterospecific enhancers. Comparisons of enhancer elements of orthologous genes between C. elegans and C. briggsae revealed extensive conservation, as well as specific instances of functional divergence. Our results indicate that functional changes in cis-regulatory sequences accumulate on timescales much shorter than the divergence of arthropods and nematodes, and that mechanisms other than conservation of individual binding sites within enhancer elements are responsible for the conservation of expression patterns of homologous genes between distantly related species.

Animals↗
PubMed2006

Origins and evolution of the recA/RAD51 gene family: evidence for ancient gene duplication and endosymbiotic gene transfer.

The bacterial recA gene and its eukaryotic homolog RAD51 are important for DNA repair, homologous recombination, and genome stability. Members of the recA/RAD51 family have functions that have differentiated during evolution. However, the evolutionary history and relationships of these members remains unclear. Homolog searches in prokaryotes and eukaryotes indicated that most eubacteria contain only one recA. However, many archaeal species have two recA/RAD51 homologs (RADA and RADB), and eukaryotes possess multiple members (RAD51, RAD51B, RAD51C, RAD51D, DMC1, XRCC2, XRCC3, and recA). Phylogenetic analyses indicated that the recA/RAD51 family can be divided into three subfamilies: (i) RADalpha, with highly conserved functions; (ii) RADbeta, with relatively divergent functions; and (iii) recA, functioning in eubacteria and eukaryotic organelles. The RADalpha and RADbeta subfamilies each contain archaeal and eukaryotic members, suggesting that a gene duplication occurred before the archaea/eukaryote split. In the RADalpha subfamily, eukaryotic RAD51 and DMC1 genes formed two separate monophyletic groups when archaeal RADA genes were used as an outgroup. This result suggests that another duplication event occurred in the early stage of eukaryotic evolution, producing the DMC1 clade with meiosis-specific genes. The RADbeta subfamily has a basal archaeal clade and five eukaryotic clades, suggesting that four eukaryotic duplication events occurred before animals and plants diverged. The eukaryotic recA genes were detected in plants and protists and showed strikingly high levels of sequence similarity to recA genes from proteobacteria or cyanobacteria. These results suggest that endosymbiotic transfer of recA genes occurred from mitochondria and chloroplasts to nuclear genomes of ancestral eukaryotes.

Animals↗
PubMed2004

Structure and function of eukaryotic DNA methyltransferases.

DNA methylation is a common epigenetic modification found in eukaryotic organisms ranging from fungi to mammals. Over the past 15 years, a number of eukaryotic DNA methyltransferases have been identified from various model organisms. These enzymes exhibit distinct biochemical properties and biological functions, partly due to their structural differences. The highly variable N-terminal extensions of these enzymes harbor various evolutionarily conserved domains and motifs, some of which have been shown to be involved in functional specializations. DNA methylation has divergent functions in different organisms, consistent with the notion that it is a dynamically evolving mechanism that can be adapted to fulfill various functions. Genetic studies using model organisms have provided evidence suggesting the progressive integration of DNA methylation into eukaryotic developmental programs during evolution.

Animals↗
PubMed2006

Classical divergence of nonlinear response functions.

The time divergence of classical nonlinear response functions reveals the fundamental difficulty of dynamic perturbation based on classical mechanics. The nature of the divergence is established for systems in regular motions using asymptotic decomposition of Fourier integrals. The asymptotic analysis shows that the divergence cannot be removed by phase-space averaging such as the Boltzmann distribution function. The implications of this study are discussed in the context of the conceptual development of quantum-classical correspondence in dynamic response.

Journal Article↗
PubMed2005

The evolution of the SEPALLATA subfamily of MADS-box genes: a preangiosperm origin with multiple duplications throughout angiosperm history.

Members of the SEPALLATA (SEP) MADS-box subfamily are required for specifying the "floral state" by contributing to floral organ and meristem identity. SEP genes have not been detected in gymnosperms and seem to have originated since the lineage leading to extant angiosperms diverged from extant gymnosperms. Therefore, both functional and evolutionary studies suggest that SEP genes may have been critical for the origin of the flower. To gain insights into the evolution of SEP genes, we isolated nine genes from plants that occupy phylogenetically important positions. Phylogenetic analyses of SEP sequences show that several gene duplications occurred during the evolution of this subfamily, providing potential opportunities for functional divergence. The first duplication occurred prior to the origin of the extant angiosperms, resulting in the AGL2/3/4 and AGL9 clades. Subsequent duplications occurred within these clades in the eudicots and monocots. The timing of the first SEP duplication approximately coincides with duplications in the DEFICIENS/GLOBOSA and AGAMOUS MADS-box subfamilies, which may have resulted from either a proposed genome-wide duplication in the ancestor of extant angiosperms or multiple independent duplication events. Regardless of the mechanism of gene duplication, these pairs of duplicate transcription factors provided new possibilities of genetic interactions that may have been important in the origin of the flower.

Algorithms↗
PubMed2004

Organization of Iroquois genes in fish.

In mammals, a total of six iroquois ( Irx) genes exist, which are organized into two clusters. Here we report on the organization of all iroquois genes present in fish, using zebrafish ( Danio rerio) and pufferfish ( Fugu rubripes and Tetraodon nigroviridis) as examples. A total of 10 Irx genes were found in pufferfish, and 11 in zebrafish; all but one of these genes are organized into clusters (four clusters plus one isolated gene locus). The "extra" fish clusters result from chromosome duplication in the fish lineage, after its divergence from tetrapod vertebrates. Two of the four fish clusters are highly conserved to the ones in mammals, with regard to similarity of genes and cluster architecture. Irx genes within the other two clusters have diverged in sequence and cluster organization, suggesting functional divergence. These results will allow us to use the zebrafish system for functional and comparative studies of iroquois genes in vertebrate development.

Animals↗
PubMed2005

Identification of three duplicated Spin genes in medaka (Oryzias latipes).

Gene and genomic duplications are very important and frequent events in fish evolution, and the divergence of duplicated genes in sequences and functions is a focus of research on gene evolution. Here, we report the identification and characterization of three duplicated Spindlin (Spin) genes from medaka (Oryzias latipes): OlSpinA, OlSpinB, and OlSpinC. Molecular cloning, genomic DNA Blast analysis and phylogenetic relationship analysis demonstrated that the three duplicated OlSpin genes should belong to gene duplication. Furthermore, Western blot analysis revealed significant expression differences of the three OlSpins among different tissues and during embryogenesis in medaka, and suggested that sequence and functional divergence might have occurred in evolution among them.

Amino Acid Sequence↗
PubMed1990

Engineering human prolactin to bind to the human growth hormone receptor.

A strategy of iterative site-directed mutagenesis and binding analysis was used to incorporate the receptor-binding determinants from human growth hormone (hGH) into the nonbinding homolog, human prolactin (hPRL). The complementary DNA for hPRL was cloned, expressed in Escherichia coli, and mutated to introduce sequentially those substitutions from hGH that were predicted by alanine-scanning mutagenesis and other studies to be most critical for binding to the hGH receptor from human liver. After seven rounds of site-specific mutagenesis, a variant of hPRL was obtained containing eight mutations with an association constant for the hGH receptor that was increased more than 10,000-fold. This hPRL variant binds one-sixth as strongly as wild-type hGH, but shares only 26 percent overall sequence identity with hGH. These studies show the feasibility of recruiting receptor-binding properties from distantly related and functionally divergent hormones and show that a detailed functional database can be used to guide the design of a protein-protein interface in the absence of direct structural information.

Amino Acid Sequence↗
PubMed2004

Functional conservation and divergence of intersex, a gene required for female differentiation in Drosophila melanogaster.

In Drosophila melanogaster, somatic sexual differentiation is regulated by a well characterized genetic hierarchy, by which the ratio of X chromosomes to autosomes (X:A) ultimately directs the deployment of sex-specific transcription factors encoded by doublesex (dsx) and fruitless (fru). In other dipterans, the X:A ratio is not the primary sex-determination signal. Correspondingly, the Drosophila hierarchy is not fully conserved. In all non-drosophilid fly species examined, Sex-lethal (Sxl), the master switch at the top of the Drosophila hierarchy, does not control somatic sex. This rapid divergence contrasts with the apparently deep conservation of dsx, which in Drosophila controls virtually all aspects of somatic sex except for male courtship behavior (which is controlled by fru). Sex-specific dsx mRNAs have been reported in Diptera, Lepidoptera and Hymenoptera, and dsx homologs in nematodes and mammals are required for aspects of male differentiation. Thus, it seems that the bottom of the hierarchy is rather ancient, especially compared with the top. To test this, we cloned insect and vertebrate homologs of the Drosophila gene intersex (ix), which functions together with dsx at the bottom of the hierarchy in females. When expressed in D. melanogaster females mutant at the endogenous ix gene, dipteran and lepidopteran ix homologs restore proper sexual differentiation, substantiating the hypothesis that ix, like dsx, is broadly conserved. When the mouse homolog is expressed it produces a dominant-negative phenotype suggesting partial functional divergence. Our results raise the possibility that a functional association between ix- and dsx-related gene products existed before the origin of the bifunctional dsx gene used in insect sex determination.

Amino Acid Sequence↗
PubMed2003

Functional respiratory chain analyses in murid xenomitochondrial cybrids expose coevolutionary constraints of cytochrome b and nuclear subunits of complex III.

The large number of extant Muridae species provides the opportunity of investigating functional limits of nuclear/mitochondrial respiratory chain (RC) subunit interactions by introducing mitochondrial genomes from progressively more divergent species into Mus musculus domesticus mtDNA-less (rho0) cells. We created a panel of such xenomitochondrial cybrids, using as mitochondrial donors cells from six murid species with divergence from M. m. domesticus estimated at 2 to 12 Myr before present. Species used were Mus spretus, Mus caroli, Mus dunni, Mus pahari, Otomys irroratus, and Rattus norvegicus. Parsimony analysis of partial mtDNA sequences showed agreement with previous molecular phylogenies, with the exception that Otomys did not nest within the murinae as suggested by some recent nuclear gene analyses. Cellular production of lactate, a sensitive indicator of decreased respiratory chain ATP production, correlated with divergence. Functional characterization of the chimeric RC complexes in isolated mitochondria using enzymological analyses demonstrated varying decreases in activities of complexes I, III, and IV, which have subunits encoded in both mitochondrial and nuclear genomes. Complex III showed a striking decline in electron transfer function in the most divergent xenocybrids, being greatly reduced in the Rattus xenocybrid and virtually absent in the Otomys xenocybrid. This suggests that nuclear subunits interacting with cytochrome b face the greatest constraints in the coevolution of murid RC subunits. We sequenced the cytochrome b gene from the species used to identify potential amino acid substitutions involved in such interactions. The greater sensitivity of complex III to xenocybrid dysfunction may result from the encoding of redox center apoproteins in both nuclear and mitochondrial genomes, a unique feature of this RC complex.

Adenosine Triphosphate↗
PubMed1991

[A case of divergence palsy associated with bilateral chronic subdural hematoma].

A surgical case of bilateral chronic subdural hematoma presenting with divergence palsy is reported. A 75-year-old female was admitted to hospital for investigation of 2-week history of diplopia. The initial neurological examination demonstrated no abnormal findings except Hess chart suggesting bilateral concomitant strabismus or paresis of lateral rectus on both eyes. Because of the homonymous diplopia disappeared when the object of fixation in brought closer and the patient showed no impairment of gaze movements and following movements, the patient was diagnosed as divergence palsy and referred to the Neurosurgical Service. The physical examination revealed a 75-year-old, alert, fully oriented with diplopia at distant gaze. A computerized tomographic (CT) scan showed bilateral subdural hematoma. Emergency burrhole evacuation was performed and total amount bilateral hematoma was 220ml. Diplopia disappeared postoperatively. Hess chart examined two months after the operation shows no impairment of divergence function. This is the first reported case of divergence palsy associated with bilateral chronic subdural hematoma in CT era.

Aged↗
PubMed1984

[Multiple forms of horse pepsin].

Using ion-exchange and affinity chromatography and isoelectrofocusing, eight forms of pepsin with pI 1.6, 1.8, 2.1, 2.3, 2.6, 2.8, 3.2 and 3.6, were isolated from horse gastric juice. The molecular weights, amino acid composition, N-terminal sequence and functional activity of these multiple forms were determined. Partial primary structure of tryptic peptides of pepsin with pI 2.3 was investigated. The analyzed partial sequences of the forms with pI 1.8, 2.1, 2.3, and 2.6 have identical structures which differ from the amino acid sequence of pepsin with pI 3.2 by four substituents. In terms of their functional activity, horse pepsins differ only insignificantly. Presumably, the pepsins under study (at least the forms with pI 1.8, 2.1, 2.3, 2.6 and 3.2) arose comparatively recently as a result of duplication of the common precursor gene and exist at an early stage of structural and functional divergence. As far as their primary structure and functional properties are concerned, these pepsins are more related to pepsin A than to other isoenzymes of gastric aspartyl proteinases of mammalia, e. g., gastricsin or chymosin.

Amino Acid Sequence↗